Exercise Alters Epigenetics

Exercise causes short-term changes in DNA methylation and gene expression in muscle tissue that may have implications for type 2 diabetes.

By Hannah Waters | March 6, 2012

FLICKR, JOINT BASE LEWIS MCCHORD

Exercise can delay the onset of diabetes by boosting the expression of genes involved in muscle oxidation and glucose regulation. A new study, published today (March 6) in Cell Metabolism, suggests that DNA methylation drives some of these changes, and that they can occur within just a few hours of exercise, providing a potential mechanism for how exercise protects the body from metabolic disease.

“It’s one of the first studies that really proves that DNA methylation can affect things in a very short timeframe,” said Marloes Dekker Nitert, who studies diabetes epigenetics at Lund University in Sweden and was not involved in the research.

People with type 2 diabetes are less responsive to insulin than healthy individuals, and thus have difficulties maintaining normal blood sugar levels. Certain metabolic genes, such as those involved in glucose transport and mitochondrial regulation, have been shown to be expressed at lower levels in diabetics, possibly explaining their decreased insulin responsiveness.

“Exercise is one therapeutic to maintain sensitivity of the organs to insulin and prevent diabetes,” said molecular physiologist Juleen Zierath of the Karolinska Institute, who in 2009 showed that diabetics have different DNA methylation patterns in muscle. This suggested “there might be some dynamic changes in methylation” after exercise, said Zierath, who teamed up with Romain Barres of Copenhagen University and others to further investigate a possible epigenetic mechanism of exercise-induced diabetes prevention.

The researchers took thigh muscle tissue samples from 14 healthy people who did not exercise regularly before and after they rode on an exercise bike for 20 minutes. Homing in on metabolic genes that tend to be expressed in lower levels in type 2 diabetics, they saw that, within three hours of exercise, promoters for these genes lost their methyl marks, making them available for transcription. Indeed, these methylation changes in turn correlated with upregulation of the genes.

“We know that the epigenome…is supposed to be quite stable,” said Ling. “This paper shows that this is a fairly dynamic process.”

The studied genes have a variety of metabolic functions. PGC-1a is a transcription factor that increases the oxidation of muscle, TFAM regulates the transcription of mitochondrial DNA, and MEF2A regulates the transport of glucose in and out of cells. “All of these genes have been previously shown to be involved with exercise,” said Charlotte Ling, an epigenetics research at Lund University, who did not take part in the study. “And they’re also connected to diabetes.”

The researchers then confirmed in vitro that the changes were due to the muscle contraction of exercise, rather than neurotransmitters or other circulating factors such as hormones. More specifically, stimulating rat muscle cells with caffeine to mimic exercise-induced calcium influx, they found that the calcium flow induced the methylation changes.

Evidence of such transient epigenetic changes is exciting, said Ling, but the changes didn’t last long: within a few more hours of the initial increases in gene expression, the muscle methylation and expression levels returned to baseline. This begs the question of whether the effects will eventually stabilize with regular exercise, she said. “If you exercise a lot and you make these epigenetic changes, you wouldn’t just change your [short-term] expression, but [in the] long-term, change your genome. And maybe you will be more protected from diabetes due to epigenetic change.”

The results suggest it may be possible to “in some way manage the metabolism of your body through a lifestyle practice,” agreed molecular exercise physiologist Perla Kaliman from the August Pi i Sunyer Biomedical Research Institute in Barcelona, who was not involved in the research. “This shows that there is some molecular evidence to support that notion that exercise is a medicine,” Zierath added.

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If muscle cells/nuclei are stimulated to divide after exercise, wouldn't DNA replication begin with an increase in unmethylated nucleotides when a population of cells in biopsies were analyzed? If methylated nucleotides became unmethylated only with exercise and not DNA replication, this would be surprising to me.

The common molecular biology across vertebrate species suggests that the epigenetic effects either of movement, or of exercise, on gene expression is due to the same mechanisms I have detailed in the context of the gene, cell, tissue, organ, organ system pathway (in accord with the FDA Critical Path Initiative and ASAM policy statement on addiction). This pathway links sensory input from the environment directly to gene activation and behavior. In mammals, for example, it is the gonadotropin releasing hormone (GnRH) neuronal system that is primarily responsible for the epigenetic effects of nutrient chemicals and species-specific pheromones on intracellular signaling and stochastic gene expression in brain tissue responsible for movement. See for example: Feedback loops link odor and pheromone signaling with reproduction. Boehm U, Zou Z, Buck LB. Cell. 2005 Nov 18;123(4):683-95.

There is no reason not to link this common pathway to epigenetic effects of exercise on muscle tissue, because the hypothalamic GnRH pulse modulates pituitary secretion of gonadotropins involved in steroidogenesis and neurotransmission. Of particular interest is the effect of food odors and pheromones on hippocampal neurogenesis, thereby linking neurotransmission to learning, and memory that is also linked to the secretion of luteinizing hormone (LH). This links 1) the requirement for movement involved in food acquisition; 2) the requirement for movement involved in mate selection; and 3) the requirement for movement and/or exercise involved in reproductive fitness to survival of individuals and to species survival in species from microbes to man.

The model is the same for the development of species specific behaviors that depend on proper nutrition and nutrient metabolism to species specific pheromones. For example, in mammals: LH is the link between sex and the sense of smell (at least until someone suggests another model based on the basic principles of biology and levels of biological organization that are required). Â

If muscle cells/nuclei are stimulated to divide after exercise, wouldn't DNA replication begin with an increase in unmethylated nucleotides when a population of cells in biopsies were analyzed? If methylated nucleotides became unmethylated only with exercise and not DNA replication, this would be surprising to me.

The common molecular biology across vertebrate species suggests that the epigenetic effects either of movement, or of exercise, on gene expression is due to the same mechanisms I have detailed in the context of the gene, cell, tissue, organ, organ system pathway (in accord with the FDA Critical Path Initiative and ASAM policy statement on addiction). This pathway links sensory input from the environment directly to gene activation and behavior. In mammals, for example, it is the gonadotropin releasing hormone (GnRH) neuronal system that is primarily responsible for the epigenetic effects of nutrient chemicals and species-specific pheromones on intracellular signaling and stochastic gene expression in brain tissue responsible for movement. See for example: Feedback loops link odor and pheromone signaling with reproduction. Boehm U, Zou Z, Buck LB. Cell. 2005 Nov 18;123(4):683-95.

There is no reason not to link this common pathway to epigenetic effects of exercise on muscle tissue, because the hypothalamic GnRH pulse modulates pituitary secretion of gonadotropins involved in steroidogenesis and neurotransmission. Of particular interest is the effect of food odors and pheromones on hippocampal neurogenesis, thereby linking neurotransmission to learning, and memory that is also linked to the secretion of luteinizing hormone (LH). This links 1) the requirement for movement involved in food acquisition; 2) the requirement for movement involved in mate selection; and 3) the requirement for movement and/or exercise involved in reproductive fitness to survival of individuals and to species survival in species from microbes to man.

The model is the same for the development of species specific behaviors that depend on proper nutrition and nutrient metabolism to species specific pheromones. For example, in mammals: LH is the link between sex and the sense of smell (at least until someone suggests another model based on the basic principles of biology and levels of biological organization that are required). Â

I'm more interested in biological facts than theories. Across species similarities in molecular biology have become clear via gene sequencing. For example, life is sustained by nutrient chemicals that cause changes in intracellular signaling and stochastic gene expression. Nutrients "calibrate" an organism's survival and are metabolized to species-specific pheromones that "standardize" and "control" speciation in species from microbes to man. Movement is required to obtain nutrients, which is required for reproduction. In microbes, reproduction is controlled by pheromones involved in quorum sensing. With the advent of sexual reproduction, desire is for the nutrient-dependent pheromones of a conspecific, which involves immune system recognition of self / non-self differences. Pheromone-enhanced desire for genetically determined non-self differences associated with diversification of species ensures survival of different species and evolution based on selection for proper nutrition and reproductive fitness in mates. As in microbes, chemical signals ensure proper selection. If Lamarck had clearly stated that nutrition allowed for genetically predisposed epigenetic changes that promote the expression of new genes for receptors activated by chemicals in novel ecological niches that change intracellular signaling and metabolism of the chemicals to pheromones, he might have been 10 years ahead of where some of us are now with regard to evolutionary theory. But being ahead means nothing when most people think that the incentive salience of visual input is more important to nutrient-dependent and pheromone-controlled physical attraction when other people are the objects of their chemically controlled desires. And most people are not likely to fully grasp the similarities in molecular biology that exist across species if they continue to think they are primarily visual creatures.

I'm more interested in biological facts than theories. Across species similarities in molecular biology have become clear via gene sequencing. For example, life is sustained by nutrient chemicals that cause changes in intracellular signaling and stochastic gene expression. Nutrients "calibrate" an organism's survival and are metabolized to species-specific pheromones that "standardize" and "control" speciation in species from microbes to man. Movement is required to obtain nutrients, which is required for reproduction. In microbes, reproduction is controlled by pheromones involved in quorum sensing. With the advent of sexual reproduction, desire is for the nutrient-dependent pheromones of a conspecific, which involves immune system recognition of self / non-self differences. Pheromone-enhanced desire for genetically determined non-self differences associated with diversification of species ensures survival of different species and evolution based on selection for proper nutrition and reproductive fitness in mates. As in microbes, chemical signals ensure proper selection. If Lamarck had clearly stated that nutrition allowed for genetically predisposed epigenetic changes that promote the expression of new genes for receptors activated by chemicals in novel ecological niches that change intracellular signaling and metabolism of the chemicals to pheromones, he might have been 10 years ahead of where some of us are now with regard to evolutionary theory. But being ahead means nothing when most people think that the incentive salience of visual input is more important to nutrient-dependent and pheromone-controlled physical attraction when other people are the objects of their chemically controlled desires. And most people are not likely to fully grasp the similarities in molecular biology that exist across species if they continue to think they are primarily visual creatures.

This is a transient signaling mechanism altering gene expression, just through DNA methylation, rather than say histone acetylation, through transcription co-factor recruitment.

The use of the term 'epigenetic' is improperly used here. There is a sad epidemic in the misuse of this word. 'Genetic'Â equates toÂ 'heritable'.Â Heritability at the organism level (i.e. the Lamarckian level)Â is related to genes (DNA and/or epigenetic marks) in gametes and their progenitors. The changes reportedÂ are occuring in muscle cells. TheyÂ are transient. But even ifÂ sustained it would lead to longer-term effects onÂ muscle cell physiology within that individual with zero impact on that individual's progeny.

Since the reported methylation changes do not affect the composition of the gametes,Â they are more akin to deletions in receptor loci in lymphocytes--a normal and necessary genetic change in an organ that is part of the physiology of an organism. Unless that change isÂ passed on to the progeny of that individual, there is nothing Lamarkian.

Epigenetic alterations in genes for odor receptors allow nutrient chemicals that metabolize to pheromones to calibrate, standardize, and control speciation. Is that Lamarckian? Is it epigenetic? Or is the epigenetics of Lamarckian inheritance merely a matter of a semantics used to deny the existence of human pheromones? From my perspective we may need another model for behavioral development and for speciation if we cannot agree on the terms commonly used in discussion of molecular biology.

This is a transient signaling mechanism altering gene expression, just through DNA methylation, rather than say histone acetylation, through transcription co-factor recruitment.

The use of the term 'epigenetic' is improperly used here. There is a sad epidemic in the misuse of this word. 'Genetic'Â equates toÂ 'heritable'.Â Heritability at the organism level (i.e. the Lamarckian level)Â is related to genes (DNA and/or epigenetic marks) in gametes and their progenitors. The changes reportedÂ are occuring in muscle cells. TheyÂ are transient. But even ifÂ sustained it would lead to longer-term effects onÂ muscle cell physiology within that individual with zero impact on that individual's progeny.

Since the reported methylation changes do not affect the composition of the gametes,Â they are more akin to deletions in receptor loci in lymphocytes--a normal and necessary genetic change in an organ that is part of the physiology of an organism. Unless that change isÂ passed on to the progeny of that individual, there is nothing Lamarkian.

Epigenetic alterations in genes for odor receptors allow nutrient chemicals that metabolize to pheromones to calibrate, standardize, and control speciation. Is that Lamarckian? Is it epigenetic? Or is the epigenetics of Lamarckian inheritance merely a matter of a semantics used to deny the existence of human pheromones? From my perspective we may need another model for behavioral development and for speciation if we cannot agree on the terms commonly used in discussion of molecular biology.